Journal of Pathology and Translational Medicine

Original Articles

The Studies of bcl-2 Oncoprotein and Epstein-Barr Virus Expression in Malignant Lymphomas: Immunohistochemical and in situ hybridization analysis on 66 cases.: Hye Jae Cho, Yeon Mee Kim, Hyun Ju Yoo, Jong Eun Joo; Korean J Pathol. 1996;30(2):121-131.

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Abstract PDF: Bcl-2 oncoprotein is being localized to mitochondria and interfering with programmed cell death (apoptosis) independent of promoting cell division in the lymphoid and nonlymphoid cells. The bcl-2 oncoprotein expression has been reported in follicular lymphomas as well as in diffuse non-Hodgkin's lymphoma, leukemia and a variable propotion of Hodgkin's lymphoma cases. Recent evidence suggests that some lymphomas protected from apoptosis is conferred through expression of Epstein-Barr virus(EBV) latent membrane protein which turn to cause upregulation of bcl-2. To define the role of the bcl-2 oncoprotein and EBV in lymphoid malignancy, we tried immunohistochemical studies with anti-bcl-2 antibody and In situ hybridization (ISH) with EBV-encoded small nuclear RNAs(EBER) in the paraffin embedded sections of 46 non-Hodgkin's lymphoma (NHL) cases and 20 Hodgkin's lymphoma (HL) cases. Bcl-2 oncoprotein expression was found in 37 of 46 cases (80%) of NHL with relatively strong cytoplasmic staining, and in 14 of 20 cases (70%) of HL with weak cytoplasmic staining in limited small numbers of RS, Hodgkin and lacunar cells. The widespread presence of bcl-2 oncogene in many different types of both NHL and HL supports that the extended cell survival through overexpression of bcl-2 gene protein may be a growth advantage of neoplastic lymphoid cells. In the ISH analysis for EBV, the presence of EBV was detected in 17 of 20 cases (85%) of HL, compared to 6 of 44 cases(13.6%) of NHL. It appears to be no direct correlation between overexpression of bcl-2 oncoprotein by neoplastic lymphoid cells and the presence of EBV in NHL but it seems to be a definite association between EBV and HL.

Epstein-Barr Virus in Korean Malignant Lymphomas.: Young Hyeh Ko, Jung Dal Lee; Korean J Pathol. 1996;30(11):1011-1017.

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Abstract PDF: To determine the prevalence of Epstein-Barr virus infection in lymphoid neoplasms of various histology and location, the paraffin tissues of 74 non-Hodgkin's lymphomas and 13 Hodgkin's diseases were studied by EBER and BHLF RNA in situ hybridization as well as immunostaining using LMP-1, EBNA-2, and ZEBRA. As a control, non-neoplastic lymphoid tissues from the nasal cavity(10), lymph node(38) and Waldeyer's ring(12) were investigated. In non-neoplastic control, EBV genome was detected in none of 10 nasal mucosa, 6 of 38 lymph node, and 1 of 12 Waldeyer's ring. EBV-positive non-neoplastic lymphocytes expressed CD45RO in 2 cases and CD20 in 4 cases. Non-Hodgkin's lymphoma was positive for EBV in 37.8% of the cases in which T-cell lymphoma showed higher rate(56%) than B-cell lymphoma(15%), especially in nasal lymphoma(80%) and angiocentric lymphoma(63.6%). Hodgkin's disease was EBV positive in 38.4% of the cases. EBV genome in tumor tissue existed in latent form as well as in lytic form. LMP-1 was positive in 80% of Hodgkin's disease and 39% of non-Hodgkin's lymphoma in which EBV genome was detected. EBNA-2 was expressed in 3 cases of non-Hodgkin's lymphoma. On the basis of protein expression, most lymphomas belonged to type II latency. These results support that EBV is associated with pathogenesis of malignant lymphoma although its mechanism still awaits to be clarified.

Expression of Phospholipase C-gamma1 and gamma2 in Non-Hodgkin's and Hodgkin's Lymphoma.: Dae Woon Eom, Sung Sook Kim, Yeong Ju Woo, Jae Hee Suh, Jooryung Huh, Ae Ran Paik, Jae Ho Kim, Sung Ho Ryu, Pann Ghill Suh; Korean J Pathol. 2000;34(2):113-118.

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Abstract PDF: Phospholipase C (PLC) plays a role in ligand-mediated signal transduction for cellular activity such as proliferation and differentiation. A recent observation that PLC- gamma1 is highly expressed in some kinds of human cancer tissue supports the view that PLC-gamma1 may be involved in proliferation and carcinogenesis. PLC-gamma2 is known to be involved in B cell differentiation and maturation. However, there have been few studies about the expressions of PLC-gamma1 and gamma2 in human lymphoid malignancy. In the present study, we examined the contents of PLC-gamma1 and gamma2 in 10 cases of B cell, 10 cases of T cell non-Hodgkin's lymphoma and 5 cases of Hodgkin's lymphoma to find out whether these enzymes play any role in the carcinogenesis by immunohistochemistry and immunoprecipitation. Immunoprecipitation analysis revealed that in contrast to increased expression of PLC-gamma2 only in B cell lymphoma, a considerably higher level of PLC-gamma1 was detected in both B and T cell lymphoma. Immunohistochemical finding confirmed this observation. PLC-gamma1 and PLC-gamma2 were expressed in the cytoplasm of most tumor cells. PLC-gamma2 was also expressed in mature B cells, while PLC-gamma1 was not expressed in reactive non-tumor cells. These results suggest that PLC-gamma1 mediated signal transduction implicates a significant role in the carcinogenesis of all types of lymphoid tissue, and PLC-gamma2 may play a role in the carcinogenesis of B cell lymphoma as well as B cell differentiation.

Inactivation Pattern of p16 Gene in Non-Hodgkin's Lymphomas.: Hyun Deuk Cho, In Sun Kim; Korean J Pathol. 2002;36(6):365-373.

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Abstract PDF: BACKGROUND
Loss of heterozygosity (LOH) and mutation of the p16 tumor suppressor gene have been detected in non-Hodgkin's lymphomas (NHLs). Recently, hypermethylation of the p16 gene has been reported. The role of p16 gene alterations in the genesis of NHLs and their high-grade transformations require explanation.
METHODS
LOH of D9S171 and IFNA microsatellite markers, DNA hypermethylation, and mutation of exon 1 and 2A were assessed in 43 cases of NHLs. The genetic abnormalities were compared with the protein expression by immunohistochemistry, and they were evaluated according to the histologic subtypes, grades and immunophenotypes.
RESULTS
DNA hypermethylation was the most common p16 gene abnormality and was found in 30 of 39 cases (76.9%). Eight cases (18.6%) showed LOH in one or both microsatellite markers, and five cases (11.6%) showed mutations in exon 1 or 2A. Loss of protein expression was seen in 17 cases (39.5%) and was associated with mutation and LOH. Loss of protein was more frequent in high-grade lymphomas than in low-grade lymphomas.
CONCLUSION
These results suggest that the functional loss of the p16 gene contributes to the development of NHLs, especially to the development of high-grade lymphomas.

Case Report

Cytologic Features of Malignant Lymphoma of the Uterine Cervix: A case report.: Nam Hoon Kim, Chan Kum Park, Young Hyeh Ko, Moon Hyang Park, Jung Dal Lee; Korean J Cytopathol. 1995;6(1):76-79.

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Abstract PDF: The uterine cervix is an uncommon site of primary non-Hodgkin's lymphoma (NHL). Although the cytologic findings of NHLs are well known, most cervicovaginal smear of uterine NHLs give lower diagnostic yield than common epithelial malignancy because abnormal cells do not appear in the sample in the absence of surface ulceration. Herein, we describe cytologic findings of a case of uterine cervical NHL which was initially diagnosed by cervicovaginal smear. The tumor cells were relatively uniform, isolated, large-sized with scanty cytoplasm and round or indented nuclei. The nuclei had stippled chromatin and small nucleoli. Histologically and immunohistochemically the tumor was proven to be large cell lymphoma of T-cell lineage.

Original Articles

Fine Needle Aspiration Cytology of Metastatic Cell Carcinoma of Lymph Nodes: Comparison to Non-Hodgkin's Lymphoma on 5 Cases.: Yeon Mee Kim, Hye Je Cho, Ill Hyang Ko; Korean J Cytopathol. 1996;7(1):44-50.

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Abstract PDF: Small cell carcinoma of the lung is characterized by cells with finely stippled chromatin and scanty cytoplasm as well as a particularly aggressive clinical course and favorable response to the chemotherapy. Recently percutaneous fine needle aspiration(FNA) biopsy has become both widely established and highly respected for the diagnosis of lung cancer. However metastatic small cell carcinoma of lymph node should be cytologically differentiated from the small round cell tumor of particular sites, especially malignant lymphoma, because small cell carcinoma of classic oat cell type may simulate small cell non-Hodgkin's lymphoma. We report five cases of metastatic small cell carcinoma of intermediate cell type diagnosed by FNA of the enlarged lymph nodes of the neck and axilla. The cytologic smears contained diffuse small neoplastic cells larger than lymphocytes with dense, pyknotic nuclei and extremely scanty cytoplasm. Apparently viable large tumor cells have vesicular nuclei with granular, sometimes very coarse chromatin. The characteristic cytologic features of small cell carcinoma as compared to malignant lymphoma were as follows.: 1) small cells with dense pyknotic nuclei are evenly distributed in the background of apparently viable larger tumor cells, admixed with mature lymphocytes and phagocytic macrophages. 2) small loose aggregates of cells with nuclear molding are indicative of small cell carcinoma rather than non-Hodgkin's lymphoma. 3) the cytoplasmic and nuclear fragments of tumor necrosis are more dominant in the smears of small cell carcinoma. 4) nuclear membrane and nucleoli are generally indistinct in small cell carcinoma due to condensation of chromatin.

Diffuse Large B Cell Lymphoma Shows Distinct Methylation Profiles of the Tumor Suppressor Genes among the Non-Hodgkin's Lymphomas.: Sun Och Yoon, Young A Kim, Yoon Kyung Jeon, Ji Eun Kim, Gyeong Hoon Kang, Chul Woo Kim; Korean J Pathol. 2008;42(1):16-20.

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Abstract PDF: BACKGROUND
Aberrant methylation of CpG islands in promoter regions is one of the major mechanisms for silencing of tumor suppressor genes in various types of human cancers including non-Hodgkin's lymphomas (NHL). In this study, we investigated the aberrant promoter methylation status of known or suspected tumor suppressor genes in NHLs and compared the methylation profiles between B-cell and T/NK-cell NHLs.
METHODS
54 cases of B-cell NHLs and 16 cases of T/NK-cell NHLs were examined for the methylation status of eight genes using methylation specific PCR.
RESULTS
CpG islands methylation was variously found in eight genes as follows; DAPK (71%), MT1G (70%), p16 (53%), CDH1 (53%), THBS1 (56%), MGMT (27.1%), COX2 (13%), and RUNX3 (11.4%). In six cases (8 %), methylation was not observed in any of these genes. Overall methylation index of B-cell NHLs (0.48) was significantly higher than that of T/NK-cell NHLs (0.32). Of eight genes tested, THBS1 and CDH1 methylations were much more prominent in diffuse large B-cell lymphomas than in T/NK-cell NHLs or other B-cell NHLs.
CONCLUSION
This study suggests that aberrant CpG island methylation is a frequent event in NHLs, and diffuse large B-cell lymphomas show overlapping but distinct methylation profiles.

Altered Expression of DNA Topoisomerase IIalpha, Ki-67, p53 and p27 in Non-Hodgkin's Lymphoma.: Kyeong Min Lee, Mee Young Sol, Hyun Jeong Kang, Dong Hoon Shin, Kyung Un Choi, Hwal Woong Kim, Jee Yeon Kim, Do Youn Park, Chang Hun Lee; Korean J Pathol. 2005;39(5):332-337.

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Abstract PDF: BACKGROUND
Topoisomerase II (TOPO II) is an enzyme that separates intertwined chromosomes during DNA synthesis by transiently breaking and joining DNA strands. The level of TOP II is one of the determinants of cellular sensitivity to anti-tumor drugs in non-Hodgkin's lymphoma patients. The alpha form of TOPO II has been recently used as a marker of cellular proliferation. High levels of TOPO IIalpha are expressed in aggressive and proliferative tumors.
METHODS
This study was designed to evaluate the relationship between TOPO IIalpha expression and clinicopathological parameters including age, gender, the serum LDH level, the serum beta2-microglobulin level and stage, or expressions, of Ki-67, p53 and p27, in non-Hodgkin's lymphoma. We analyzed forty-one biopsied tissue specimens from patients with non-Hodgkin's lymphoma.
RESULTS
The expression of TOPO IIalpha increased with the clinical stage and it was correlated with Ki-67 and p53 expressions. However, TOPO IIalpha expression did not have any significant correlation with age, gender, the serum LDH level, the serum 2-microglobulin level and the p27 expression.
CONCLUSIONS
TOPO IIalpha expression is a useful marker of cellular proliferation and it may serve as a prognostic factor of a tumor's progression and aggressiveness in non-Hodgkin's lymphomas.

CD30 (Ber H2) Distribution in Hodgkin's Disease and non-Hodgkin's Lymphoma.: Bong Hee Kim, Young Hee Maeng, Ju Hie Lee, Moon Ho Yang; Korean J Pathol. 1994;28(4):381-388.

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Abstract PDF: Forty one cases of Hodgkin's disease and non-Hodgkin's lymphomas were immunohisto-chemi-cally studied for the presence of CD30 antigen on the paraffin embedded formaldehyde fixed tissue by using Ber H2(CD30) monoclonal antibody (Dakopatts, diluted l : 20) and avidin biotin peroxidase complex technique seventy five %(6/8) of Hodgkin's lymphoma and 27% (9/33) of non-Hodgkin's lymphomas were CD30 positive. Five of l7 diffuse large cell and immunoblastic lymphoma and one large cell anaplastic lymphoma showed large numbers of CD30 positive cells. Occasional CD30 positive cells were found in one of 2 angiommunoblastic lymphadenopathy-like T cell lymphoma, one of 4 small lymphocytic lymphoma and one unclassified lymphoma. Immunophenotypically l6% of B cell lymphoma and 42% of T cell lymphoma showed CD30 positivity. six cases of Hodgkin's disease except lymphocyte predominance showed positive tumor cells. Our results show that CD30 is more widespread in histologic subtypes of lymphomas and is not specific for the diagnosis of Hodgkin's disease.

Case Report

Primary Cerebral B Cell Lymphoma: A "ghost tumor" case report.: Hye Jae Cho, Jung Won Shim, Sang Keun Park, Joon Suk Song, Gham Hur, Hyun Sook Seo; Korean J Pathol. 1991;25(1):68-75.

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Abstract PDF: Primary non-Hodgkin's lymphoma of the brain is a rare malignancy and there are known to occur almost exclusively in brain parenchyme. Recent immunological advances and immunohistochemical techniques have provided new insights into the pathogenesis and diagnosis of the malignant lymphoma even in the small biopsied tissue and the majority of these CNS tumors is thought to be derived from B lymphocytes. A 22-year old man was admitted due to headack, dizziness and walking difficulty for 2 months. On the initial CT scan, there were two enhancing lesion in the suprasellar area and pineal gland which were completely disappeared with steroid therapy and three new lesions appeared on the follow-up CT and MRI studies in corpus callosum, third ventricle and left cerebral peduncle. The serial cytologic smears of cerebrospinal fluid and a stereotaxic biopsy tissue from the corpus callosum mass showed diffusely homogenous infiltration of neoplastic large noncleaved lymphocytes with focal perivascular arrangement. On the immunocytochemical stains, the reaction was negative for GFAP, positive for LCA and MB2, and negative for MT1. After radiation therapy, the masses completely disappeared on the follow-up CT scan and the patient was discharged free of all the clinical symptoms.

Original Article

Histopathological Studies of 300 Cases of Non-Hodgkin's Lymphoma in Korean Patients.: Hee Jeong Ahn, Soon Hee Jung, Hyen Joo Jeong, Dong Hwan Shin, Kwang Gil Lee, In Joon Choi; Korean J Pathol. 1988;22(3):222-231.

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Abstract PDF: Non-Hodgkin's malignant lymphoma is a relatively frequent lymphoreticular malignancy, and has been reported to constitute up to 5.2% of all malignant tumors in Korean patients. Various morphologic classifications of non-Hodgkin's lymphoma have been proposed, and among them, the Rappaport's classification has been most widely accepted. In 1982, a National Cancer Institute sponsored study on classification led to the creation of the Working Formulation in an attempt to resolve the controversy anddebate regarding the various classifications of non-Hodgkin's lymphoma. Angioimmunoblastic lymphadenopathy with dysproteinemia and polymorphic reticulosis are lymphoreticular proliferative disorders which have reported to transform to malignant lymphoma. The purpose of the present study is to reclassify non-Hodgkin's lymphomas according to the Working Formulation and to investigate the histopathological and immunocytochemical characteristics of angioimmunoblastic lymphadenopathy with dysproteinemia and polymorphic reticulosis. This study reviewed 300 cases of nodal and extranodal non-Hodgkin's lymphoma, 26 cases of polymorphic reticulosis, and 7 cases of angioimmunoblastic lymphadenopathy with dysproteinemia examined in the Departments of Pathology, Yonsei University College of Medicine, Youngdong Severance Hospital and Yonsei University Wonju College of Medicine from January 1977 to December 1986. In non-Hodgkin's lymphoma, each case was classified according to the Working Formulation and the Rappaport classification. All angioimmunoblastic lymphadenopathy with dysproteinemia and polymorphic reticulosis cases were subjected to histopathological analysis and a review of the clinical records. Immunocytochemical studies were done using kappa and lambda chains for B-cell markers and alpha-1-antichymotrypsin for histiocytic marker. The results obtained were as follows; 1) Among 300 cases of non-Hodgkin's lymphoma, the primarily involved tumor sites were the lymph nodes (141 cases), the gastrointestinal tract (67 cases), and the tonsils (32 cases) in descending order of frequency. 2) Using the Working Formulation, intermediategrade lymphomas occurred in 66.4% of the patients, and the most common subtype was "diffuse, large cell" (32.7%). By the Rappaport classification, 3 patients had nodular lymphomas, and "diffuse, histiocytic" was the most common subtype. 3) Infarction was present in 32 cases in which the "diffuse, lagre cell" type was most frequently associated. 4) In immunoperoxidase stains of 7 cases of angioimmunoblastic lymphadenopathy with dysproteinemia, proliferating immunoblasts revealed a polyclonal positivity for kappa and lambda chains. Atypical reticulocytes present in 26 cases of polymorphic reticulosis revealed a negativity for kappa, lambda and alpha-1-antichymotrypsin.

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